DESCRIPTION: (Verbatim from the Applicant's Abstract) Adolescence, the period roughly between onset of puberty and emergence of full adulthood, is a time when the mammalian brain undergoes substantial change. The metabolic rate of the CNS sharply declines, and we loose about 40 percent of our synaptic contacts in a dramatic process of remodeling in which axons, dendrites, synapses, and receptors overproduced in the prepubertal period are pruned back to adult configuration. Surprisingly, this as been a poorly explored period of CNS development, although these changes almost certainly have implications for our understanding of neuropsychiatric disorders. For instance, most cases of schizophrenia emerge between adolescence and early adulthood, and some etiological theories postulate that schizophrenia arises from excessive pruning. Puberty also represents a transition period during which time stimulant medications begin to take on a euphoriant potential absent earlier in childhood (Rapoport et al 1980). Adolescence is also a period of gain, in which there is a marked decrease in prevalence of Tourette's Disorder, epilepsy, and many cases of Attention Deficit/Hyperactivity Disorder (ADHD) remit or lose hyperactive symptoms. The aim of this proposal is to systematically investigate neuropharmacological changes that occur in the ascending dopamine (DA) system during the peripubertal period. DA is a primary focus as dopaminergic drugs play a pivotal role in treatment of schizophrenia, Tourette's Disorder, and ADHD, and stimulants exert powerful effects on DA neurotransmission. During the previous period of support we discovered that there were prominent gender differences in DA system development, which provides new insight into why males are more likely to develop Tourette's Disorder, ADHD, and to abuse stimulants. We propose to test the hypotheses that: 1) overproduction of striatal DA receptors in male but not female rats is mediated by testosterone through an androgen receptor; 2) elimination of over produced DA receptors in male striatum and prefrontal cortex of both genders requires activation of NMDA receptors and displays a critical period; 3) a potential purpose of DA receptor rearrangement during perioadolescent period is to fine tune the afferents and efferents of the striatal spiny neuron; 4) that local intrinsic circuits in PFCTX changes substantially in the peripubertal period; and 5) that estrogen exerts robust peripubertal effects on serotonin neurotransmission in the nucleus accumbens which may have implications regarding emergence and treatment of mood, anxiety disorders, and suicide.